Myeloid Mas drives pyruvate kinase M2-mediated Spi1 lactylation to fuel inflammatory senescence in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is driven by unresolved inflammation, yet precise mechanisms linking immune metabolism to disease progression remain elusive. Here, we identified myeloid-expressed Mas, a G protein-coupled receptor, as a critical metabolic checkpoint in MASLD. Mas expression is elevated in hepatic myeloid cells from patients and diet-induced mouse models. Myeloid-specific Mas1 deletion attenuated MASLD by restraining glycolytic reprogramming and inflammatory senescence. Single-cell RNA sequencing analyses revealed that this deletion specifically impaired the glycolytic flux and subsequent pathogenic differentiation of FN1⁺CCR2⁺ monocyte precursors. Mechanistically, Mas interacts with the glycolytic enzyme PKM2, enhancing lactate production that drives lactylation of the transcription factor Spi1 at lysine 208. Spi1-K208 lactylation promotes its nuclear localization and transcriptional activation of senescence-associated secretory phenotype (SASP) genes. Myeloid-specific Pkm2 ablation phenocopied the protective effect of Mas1 deletion, and PKM2 overexpression rescued the metabolic and transcriptional defects caused by Mas loss. Virtual screening identified theaflavin-3,3'-digallate (TFDG) as a Mas inhibitor that disrupts the Mas-PKM2 interaction. A macrophage membrane-coated nanoparticle (MM@NP-TFDG) delivered TFDG specifically to hepatic macrophages, suppressed the Mas-PKM2-Spi1 lactylation axis, and ameliorated MASLD pathology in vivo. Our findings define a novel Mas-PKM2-Spi1 lactylation axis that orchestrates glycolytic reprogramming, monocyte precursor differentiation, and macrophage-driven inflammation in MASLD, presenting a targeted nanotherapeutic strategy for its treatment.